CTRI

In the fight against relapsed and refractory ALL, niclosamide, a drug that was once used to treat tapeworm infections, has shown promise. According to a number of studies that have extensively documented the pleiotropic effects of this drug, it may be able to target particular weaknesses in leukemia cells. Niclosamide has been reported to alter many oncogenic signaling pathways and modulate key phenomena pertinent to cancer progression such as apoptosis, autophagy and even modulation of the tumor immune microenvironment. Despite its potential, the use of niclosamide still faces a number of challenges. These include addressing possible adverse effects, better understanding its methods of action, and maximizing its delivery to cancer cells. The best niclosamide dosage, timing, and combination therapies for the treatment of ALL require more investigation.

Rationale:
In acute leukemia, evasion of apoptosis leads to chemotherapy resistance and treatment failure. Research on the in vivo function of apoptosis in leukemia cells and the application of anti-apoptotic medications in the management of ALL is, however, scarce. According to the initial findings of our ongoing research (ICMR Adhoc grant) on the role of the apoptosis pathway in ALL, patients with a low baseline apoptosis index have a poor post-induction remission rate. In order to treat R/R ALL, we intend to alter the apoptosis pathway using Niclosamide, a repurposed anthelminthic medication with immunomodulatory and broad anti-cancer properties.

Niclosamide, a well-known anthelminthic drug with a unique mechanism of action, offers a promising therapy due to its ability to affect multiple cellular processes. By reprogramming cellular metabolism and acting as a mitochondrial uncoupler, niclosamide modulates the global epigenetic landscape, allowing it to suppress oncogenic pathways while enhancing tumor suppressor pathways. Given its capacity to target several pathways simultaneously, it may bypass the usual resistance mechanisms seen with conventional therapies, providing a novel therapeutic approach for R/R ALL.

Novelty:
The innovative aspect of this study lies in repurposing niclosamide, an anti-parasitic drug, as a potential therapy for R/R ALL. Unlike traditional chemotherapy, which targets rapidly dividing cells and often leads to resistance, niclosamide uniquely reprograms cellular metabolism and modulates epigenetic landscapes, offering a dual effect of inhibiting cancer-promoting pathways and activating cancer-suppressing pathways. Preclinical evidence in T-ALL xenograft models, showing activation of apoptotic markers such as cleaved caspase-3 and autophagy markers like LC3B, further highlights its novel mechanism of action. This approach could open pathways to a new class of treatments for R/R ALL, particularly in resource-limited settings where access to newly developed, expensive oncology drugs is restricted.

Expected Outcome:

It is anticipated that niclosamide will demonstrate a significant anti-leukemic effect in R/R ALL by activating both apoptotic and autophagy pathways, leading to reduced leukemic cell proliferation and improved survival outcomes in patients. Additionally, it is expected that it’s immune-modulation effect will lead to better clinical outcomes. Potentially establish niclosamide as an accessible and cost-effective therapeutic alternative for R/R ALL, especially valuable in resource-constrained environments. Biomarkers of drug response identified through the study will help in better patient selection for future studies and clinical use. Additionally, the findings may encourage further research into the metabolic reprogramming and epigenetic effects of niclosamide, expanding its applicability beyond ALL to other resistant cancer types.